Fibrosis is a disease characterized by excessive deposition of connective tissue proteins contributing to abnormal extracellular matrix (ECM) metabolism in organs such as skin, lungs, heart, liver, kidney, etc. Fibrosis can reduce the number of healthy cells in any organs or tissues. Also, an increase in mass of fibrotic connective tissues may cause damage to normal structures of the organs or tissues. Such damage may weaken the physiological and biochemical functions of the affected organs or tissues, and completely ruin the organs. Research on pathology, diagnostic methods, preventive and therapeutic methods for treating fibrosis in organs and tissues has been widely conducted. However, there are still many challenges, especially in the field of development of effective therapeutic agents.
A mechanism of fibrosis formation has not been sufficiently elucidated so far. However, the fibrosis in the organs and tissues is generally caused by combined factors, for examples, inflammations, immunological responses, ischemia, hemodynamic changes, etc. (which result in inflammatory degeneration and necrosis in soft tissue cells). As a result, the affected soft tissue cells activate macrophages to release a large number of cytokines and growth factors. Among these, transforming growth factor-beta (TGF-β) plays an important role. TGF-β can activate the resting ECM components to generate cells, which can be converted into myofibroblasts. The newly formed fibroblasts increase the production of collagen that is a core protein of ECM, and also decrease the destruction of ECM. As a result, the ECM components are accumulated, thereby inducing the formation of fibrosis in organs or tissues. Thus, the onset and progression of fibrosis in organs or tissues result from inflammatory responses and the production of inflammatory cytokines, mainly TGF-β. Owing to the critical role of TGF-β in the ECM accumulation and the formation of fibrosis in the organs or tissues, it was logically an important goal to screen for compounds capable of inhibiting the production of pro-inflammatory cytokines, TGF-β, in an early stage of development of anti-fibrotic drugs.
Meanwhile, dimethylfumarate (DMF) is known as a substance that activates a transcriptional regulatory factor, Nrf2, which plays an important role in the production of antioxidant enzymes and phase II detoxification enzymes in cells in response to external oxidative stress. Also, DMF is a drug that is used to treat skin diseases such as psoriasis, has a therapeutic effect in treating multiple sclerosis, and is in a clinical trial stage. Also, DMF is reported to inhibit the metastasis of cancer and suppress the proliferation of cancer cells, but no research on DMF having an effect in treating and improving renal fibrosis has yet been reported.
Accordingly, the present inventors have made a great effort to develop novel therapeutic agents for treating renal fibrosis, and found that DMF has an effect in alleviating renal fibrosis by activating Nrf2. Therefore, the present invention has been completed based on these facts.